CN1426396A - Substituted benzoic acid amides and use for inhibition of angiogenesis thereof - Google Patents

Substituted benzoic acid amides and use for inhibition of angiogenesis thereof Download PDF

Info

Publication number
CN1426396A
CN1426396A CN01808600A CN01808600A CN1426396A CN 1426396 A CN1426396 A CN 1426396A CN 01808600 A CN01808600 A CN 01808600A CN 01808600 A CN01808600 A CN 01808600A CN 1426396 A CN1426396 A CN 1426396A
Authority
CN
China
Prior art keywords
alkyl
group
represent hydrogen
halogen
perhaps
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN01808600A
Other languages
Chinese (zh)
Other versions
CN1285578C (en
Inventor
安德烈亚斯·胡特
迪特尔·塞德曼
卡尔－海因茨·蒂尔奥赫
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of CN1426396A publication Critical patent/CN1426396A/en
Application granted granted Critical
Publication of CN1285578C publication Critical patent/CN1285578C/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Rheumatology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Transplantation (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)

Abstract

The invention relates to the substituted benzoic acid amides of the formula (I) and to their use as medicaments for treating diseases caused by persistent angiogenesis, and to the intermediates thereof for producing the inventive benzoic acid amides.

Description

Substituted benzoic acid amides and the application in suppressing vasculogenesis thereof
Technical field
The present invention relates to substituted benzoic acid amides and, also relate to the intermediate product that is used to prepare benzoic amide as the application of treatment by the medicine of the disease of persistence vasculogenesis initiation.
Background technology
The persistence vasculogenesis can be the inducement of various diseases, psoriasis for example, sacroiliitis such as rheumatoid arthritis, vascular tumor, hemangiofibroma, ophthalmic such as diabetic retinopathy, neovascular glaucoma, ephrosis such as glomerulonephritis, diabetic nephropathy, pernicious renal necrosis, embolic microangiopathy syndromes, graft rejection reaction and glomerulopathy, fibrotic conditions such as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis perhaps can cause the deterioration of above-mentioned disease.
Directly or indirectly suppressing VEFG acceptor (VEFG=vascular endothelial growth factor) can lure and draw treatment these diseases and other and generated and vascular permeability illness such as tumor-blood-vessel growth by the pathologic vessels that VEFG brings out.For example, the antibody of available soluble receptors of the growth of known cancer and anti-VEGF suppresses.
The persistence vasculogenesis is brought out by its acceptor by factor VEFG.For making VEFG can bring into play this effect, VEFG must be bonded on the acceptor, and brings out tyrosine phosphorylation.
The derivative that is not included in the compound in the scope of the invention has been described to calpain inhibitor (WO 9823581, and WO 9825883), PLA 2 inhibitors (WO 9700583), PGD2 antagonist (WO 9700853), neurokinin A antagonist (WO 9516682), tranquilizer (US 3892752) or anoretics (FR 1600541).
The effect that these known compounds are relevant with VEGF was not described in the past.
Summary of the invention
Have now found that the compound of general formula I and isomer thereof and salt can make tyrosine phosphorylation or persistence vasculogenesis stop, and prevent growth of tumor and breeding thus: Wherein: A represents group=NR 7, W represents oxygen, sulphur, two hydrogen atoms or group=NR 8, Z represents a key, group=NR 10Perhaps=N-, straight chain or side chain C 1-12Alkyl or
Following group: M, n and o represent 0-3, R a, R b, R c, R d, R e, R fRepresent hydrogen, fluorine, C respectively independently 1-4Alkyl or group
=NR 10, and/or R aAnd/or R bWith R cAnd/or R dForm a key or R cWith R eAnd/or
R fForm key, perhaps a radicals R a-R fIn maximum two can closure have maximum 3 carbon
The bridge of atom forms R respectively 1Perhaps form R 7, R 1Representative is chosen wantonly in one or more position by halogen or C 1-6The straight chain that alkyl replaces or
Person's side chain C 1-6Alkyl, C 2-12Thiazolinyl or C 3-12Alkynyl, perhaps representative is chosen wantonly at one
Perhaps a plurality of positions are by halogen or C 1-6The C that alkyl replaces 3-10Cycloalkyl or C 3-10
Cycloalkenyl group, perhaps representative is chosen wantonly in one or more position by halogen, C 1-6Alkyl,
C 1-6Alkoxyl group or the C that is replaced by halogen in one or more position 1-6Alkyl
Or C 1-6Aryl or heteroaryl that alkoxyl group replaces, R 2And R 3Represent hydrogen, OH group or radicals X R 11, X represents C 2-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Represent monocyclic aryl, aryl bicyclic or heteroaryl, they can be unsubstituted or choose wantonly one
Individual or a plurality of positions are by halogen, C 1-6Alkyl, C 1-6Alkoxyl group or hydroxyl replace, R 4, R 5And R 6Represent hydrogen, halogen or do not replace or in one or more position by halogen
The plain C that replaces 1-6Alkoxyl group, C 1-6Alkyl or C 1-6Carboxyalkyl, perhaps R 4And R 5
Form following group together:
Figure A0180860000091
R 7Represent hydrogen or C 1-6Alkyl or with Z in R a-R fPerhaps to R 1Formation contains maximum 3
The bridge of individual annular atoms, R 8And R 10Represent hydrogen or C 1-6Alkyl, wherein R 2And R 3Represent hydrogen, but different times table hydrogen,
If R 2Represent the OH group, then R 3Do not represent hydrogen, and if R 3Represent the OH base
Group, then R 2Do not represent hydrogen, and R 1It must not thiazole.
Embodiment
If R 7Be formed up to R 1Bridge, then produce R 1Condense heterogeneous ring compound thereon.For example, they can be:
If R a, R b, R c, R d, R e, R fRepresent hydrogen or C respectively independently 1-4Alkyl, then Z-shaped one-tenth alkyl chain.
If R aAnd/or R bWith R cAnd/or R dPerhaps R cAnd/or R dWith R eAnd/or R fForm a key, then Z represents thiazolinyl or alkynyl.
R a-R fForm a bridge, then Z representation ring alkyl or cycloalkenyl group with itself.
If R a-R fIn maximum two formation bridge of having maximum 3 carbon atoms form R 1, then Z and R 1Be that benzo-fused or assorted fragrance condenses (Ar) cycloalkyl together.
For example can be following group:
If radicals R a-R fIn one of closed bridge form R 7, then form by a group and R 1Nitrogen heterocyclic separately.
For example can be following group:
Alkyl is defined as straight chain or branched-chain alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl or hexyl, wherein preferred C 1-4Alkyl.
Cycloalkyl is defined as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl, ring octyl group, ring nonyl or ring decyl.
Cycloalkenyl group is defined as cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base, cyclonoene base or cyclodecene base, but wherein key is connected on two keys and the singly-bound.
Halogen is defined as fluorine, chlorine, bromine or iodine.
Thiazolinyl and alkynyl substituted base respectively are straight chain or side chain, and comprise 2-6, preferred 2-4 carbon atom.For example, can be following group: vinyl, propylene-1-base, propylene-2-base, but-1-ene-1-base, but-1-ene-2-base, but-2-ene-1-base, but-2-ene-2-base, 2-methyl-third-2-alkene-1-base, 2-methyl-third-1-alkene-1-base, but-1-ene-3-base, ethynyl, third-1-alkynes-1-base, fourth-1-alkynes-1-base, fourth-2-alkynes-1-base, fourth-3-alkene-1-base and allyl group.
Aryl has 6-12 carbon atom, for example naphthyl, xenyl and particularly preferred phenyl.
Heteroaryl can be benzo-fused.For example, as 5 yuan of assorted aromatic compounds, can be thiophene, furans, oxazole, thiazole, imidazoles and benzo derivative thereof, and, can be pyridine, pyrimidine, triazine, quinoline, isoquinoline 99.9 and benzo derivative thereof as 6 yuan of assorted aromatic compounds.
Aryl and heteroaryl can be 1,2 or 3 position in identical or different modes by halogen, C 1-4Alkoxyl group, nitro, trifluoromethyl, trifluoromethoxy, cyano group, SO qR 5Or C 1-4Alkyl replaces, and wherein q represents 0-2.
If comprise acidic group, organic and physiology compatible salt mineral alkali is suitable salt, for example be easy to dissolved an alkali metal salt and alkaline earth salt and N-methyl-glycosamine, dimethyl-glycosamine, ethyl-glycosamine, Methionin, 1,6-hexanediamine, thanomin, glycosamine, sarkosine, serinol, trishydroxymethyl-amino-methane, aminopropane glycol, Sovak alkali and 1-amino-2,3,4-butane triol.
If comprise base, organic and physiology compatible salt mineral acid is suitable, for example hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartrate, fumaric acid etc.
Formula I compound that proof is following and isomer thereof and salt are effective especially, and wherein: A represents group=NR 7, W represents oxygen, sulphur or two hydrogen atoms, and Z represents a key, group=NR 10Perhaps straight or branched C 1-12Alkyl R 1Representative is chosen wantonly in one or more position by halogen or C 1-6The straight chain that alkyl replaces or
Person's side chain C 1-6Alkyl, perhaps representative choose wantonly in one or more position by halogen or
C 1-6The C that alkyl replaces 3-10Cycloalkyl, perhaps the representative be unsubstituted or choose wantonly one or
The a plurality of positions of person are by halogen, C 1-6Alkyl, C 1-6Alkoxyl group or at one or many
The C that individual position is replaced by halogen 1-6Alkyl or C 1-6Phenyl, pyridine that alkoxyl group replaces
Base, naphthyl, quinolyl, isoquinolyl, indanyl, 1,2,3,4-tetralin base,
Indyl, thienyl, indazolyl or benzothiazolyl, R 2And R 3Represent hydrogen, OH group or radicals X R 11, X represents C 2-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Representative does not replace or chooses wantonly in one or more position by halogen, C 1-6Alkoxyl group or
Phenyl, pyrimidyl or pyridyl that person's hydroxyl replaces, R 4, R 5, R 6And R 7Represent hydrogen, R 8And R 10Represent hydrogen or C 1-6Alkyl, wherein R 2And R 3Represent hydrogen, but different times table hydrogen,
If R 2Represent the OH group, then R 3Do not represent hydrogen, and if R 3Represent the OH base
Group, then R 2Do not represent hydrogen.
Also formula I compound below the proof and isomer thereof and salt are effective especially, and wherein: A represents group=NR 7, W represents oxygen or one or two hydrogen atom, and Z represents a key, group=NR 10Perhaps straight chain or side chain C 1-12Alkyl R 1Represent straight chain or side chain C 1-6Alkyl, perhaps representative is chosen wantonly in one or more position
By halogen or C 1-6The C that alkyl replaces 3-10Cycloalkyl, perhaps representative is unsubstituted or appoints
Be selected in one or more position by halogen, C 1-6Alkyl, C 1-6Alkoxyl group or
The C that one or more position is replaced by halogen 1-6Alkyl or C 1-6Alkoxyl group replaces
Phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indenyl, 1,2,3,4-four
Hydrogenation naphthyl, indyl, thienyl, indazolyl or benzothiazolyl, R 2And R 3Represent hydrogen, OH group or radicals X R 11, X represents C 2-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Representative does not replace or chooses wantonly in one or more position by halogen, C 1-6Alkoxyl group or
Phenyl, pyrimidyl or pyridyl that person's hydroxyl replaces, R 4, R 5, R 6And R 7Represent hydrogen, R 8And R 10Represent hydrogen or C 1-6Alkyl, wherein R 2And R 3Represent hydrogen, but different times table hydrogen,
If R 2Represent the OH group, then R 3Do not represent hydrogen, and if R 3Represent the OH base
Group, then R 2Do not represent hydrogen.
Can prevent phosphorylation according to compound of the present invention, that is to say that some Tyrosylprotein kinase can optionally be suppressed, the persistence vasculogenesis is stopped.Therefore, for example can prevent growth of tumor and breeding.
Also can comprise possible tautomer and comprise E-or the Z-isomer according to compound of Formula I of the present invention,, also can comprise raceme and enantiomorph if perhaps there is chiral centre.
The compound of formula I and physiology compatible salt thereof are owing to have the activity of inhibition, useful as drug with respect to the phosphorylation of vegf receptor.Based on its binding mode, compound according to the present invention is suitable for treating the disease that is caused by the persistence vasculogenesis.
Because determine that the compound of formula I is the inhibitor of Tyrosylprotein kinase KDR and FLT,, they increase the disease that is caused via persistence vasculogenesis or vascular permeability that vegf receptor causes so being particularly suitable for treating those.
The present invention also comprises the purposes of compound according to the present invention as the inhibitor of Tyrosylprotein kinase KDR and FLT.
Therefore, the present invention also is provided for treating medicine or its purposes of tumour.
Can use or be used for preparation separately according to compound of the present invention, medicament as the following disease of treatment: psoriasis, sacroiliitis such as rheumatoid arthritis, vascular tumor, hemangiofibroma, ophthalmic such as diabetic retinopathy, neovascular glaucoma, ephrosis such as glomerulonephritis, diabetic nephropathy, pernicious renal necrosis, embolic microangiopathy syndromes, graft rejection reaction and glomerulopathy, fibrotic conditions such as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis, and neural tissue injury.
In treatment during neural tissue injury, can prevent from quick cicatrization on the damage location to that is to say with compound of the present invention, before reconnecting, aixs cylinder prevents the generation of cicatrization.Therefore help the reconstruction of nerve component.
Also can suppress the formation of ascites among the patient with compound according to the present invention.Also can suppress the edema that VEGF brings out.
These medicines, its preparation and purposes are also included within the scope of the present invention.
Therefore, the compound that the invention still further relates to general formula I is used for the treatment of application in the medicine of following disease in preparation: tumour, psoriasis, sacroiliitis such as rheumatoid arthritis, vascular tumor, hemangiofibroma, ophthalmic such as diabetic retinopathy, neovascular glaucoma, ephrosis such as glomerulonephritis, diabetic nephropathy, pernicious renal necrosis, embolic microangiopathy syndromes, graft rejection reaction and glomerulopathy, fibrotic conditions such as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis, and the damage of nervous tissue.
At the compound that uses general formula I during as medicine, can be made into pharmaceutical preparation, except that activeconstituents, said preparation also can comprise suitable medicinal organic or inorganic inert material when being used for enteron aisle or parenteral administration, as water, gelatin, gum arabic, lactose, starch, Magnesium Stearate, talcum, vegetable oil, polyalkylene glycol etc.Pharmaceutical preparation can be solid dosage, and for example tablet, coated tablet, suppository, capsule perhaps are liquid dosage form, for example solution, suspensoid or emulsion.They can choose salt or the buffer reagent that comprises adjuvant such as sanitas, stablizer, wetting agent or emulsifying agent, changes osmotic pressure wantonly.
When parenteral administration, injection liquid or suspension, the especially aqueous solution of active compound in poly-hydroxyl-oxethyl Viscotrol C is suitable.
As carrier system, also can use the salt or the animal or plant phosphatide of surfactivity adjuvant such as cholic acid, also comprise their mixture and liposome or component.
When oral administration, the tablet, coated tablet or the capsule that contain talcum and/or hydrocarbon carrier or tackiness agent such as lactose, W-Gum or yam starch are suitable.The also available liquid dosage form of administration carries out, as the optional juice that is added with sweeting agent.
The dosage of activeconstituents can be determined according to similar factors such as the type of medication, patient's age and body weight, disease to be treated and severity.Every day, dosage was 0.5-1000mg, was preferably 50-200mg, and this dosage can the disposable administration of single dosage or is divided into 2 or more a plurality of per daily dose administration.
Above-mentioned preparation and form of administration are also within the scope of the invention.
Preparing compound of the present invention can carry out according to method known to those skilled in the art.For example, the compound of formula I is following to be made: (a) in general formula I I compound, R wherein 4-R 6Identical with above definition, A is halogen or OR 11, and R 11Represent hydrogen, C 1-4Alkyl or C 1-4Acyl group, R 2 'And R 3 'Represent hydrogen, aldehyde, halogen or OH, O-triflate (triflate), O-tosylate or O-methanesulfonates, at first with R 2 'And R 3 'Be converted into alkenyl or alkynyl, choosing wantonly saturated is corresponding alkane, then COA is converted into acid amides,
Perhaps (b) randomly is reduced to ketone group alcohol or alkane then with the compound acylations of general formula III, removes protecting group, and amine is converted into nitrile, then with the nitrile saponification and be converted into acid amides,
Figure A0180860000171
R wherein 4-R 6Identical with above definition, T represents protecting group.
The order of reactions steps can exchange mutually.
The formation of acid amides can be carried out according to known method in the document.
For the formation of acid amides, can be initial by corresponding ester.According to J.Org.Chem.1995,8414 method is being reacted described ester and trimethyl aluminium and corresponding amine in solvent such as toluene under the temperature of 0 ℃-solvent boiling point.If molecule comprises two ester groups, then they all can be converted into identical acid amides.
When using nitrile to substitute ester, similarly obtaining amidine under the condition.
But,, also can use all known methods in the chemistry of peptides for the formation of acid amides.For example, corresponding acid can be reacted in aprotic polar solvent such as dimethyl formamide with amine, wherein pass through activated acid derivatives, this derivative can be for example obtains with hydroxybenzotriazole and carbodiimide such as di-isopropyl carbodiimide, perhaps use preformed reagent such as HATU (Chem.Comm.1994,201) or BTU obtain, temperature of reaction is the boiling temperature of 0 ℃-solvent, is preferably 80 ℃.For the formation of acid amides, also can use mixed acid anhydride, imidazolidine (imidazolide) or trinitride in the method.
If in the presence of Friedel-Crafts catalyzer such as boron trichloride, corresponding phenol and isocyanic ester or lsothiocyanates are reacted in solvent such as toluene, temperature is the boiling temperature of 0 ℃-solvent, then obtains salicylic amide.
If in molecule, introduce various amide group, for example, can introduce second ester group amidation then in molecule behind first amide group of preparation, perhaps group is an ester and another group is acid sequentially to make this two group amidations according to the whole bag of tricks then in the molecule.
According to Bull Soc.Chim.Belg.87,229,1978, with diphosphadithianes reaction, perhaps in such as the solvent of pyridine or even do not have under the situation of solvent, react with thiophosphoric anhydride down in 0-200 ℃, can make thioamides thus.
Product also can carry out electrophilic aromatic substitution.This substitution reaction occurs among the neighbour or contraposition of formula III compound, is converted into amino (then being converted into formula II compound in a position), forms carbonyl.Like this; can be in the presence of Friedel-Crafts catalyzer such as aluminum chloride; in solvent such as Nitromethane 99Min., dithiocarbonic anhydride, methylene dichloride or oil of mirbane, under the boiling temperature of 0 ℃-solvent, preferred room temperature, carry out the Friedel-Crafts acylations with acyl chlorides.According to known method in the document, under situation without solvent, the nitric acid by nitration acid, various concentration for example, perhaps by metal nitrate such as cupric nitrate (II) or iron nitrate (III), in polar solvent such as ethanol or glacial acetic acid or diacetyl oxide, can introduce one or more nitro.
Can introduce halogen according to known method in the document, for example in polar solvent such as tetrahydrofuran (THF), acetonitrile, methylene dichloride, glacial acetic acid or dimethyl formamide, react with bromine, N-bromo or N-iodosuccinimide or utropin hydrotribromide.
The reduction of nitro can be carried out under room temperature or high temperature in polar solvent.As the catalyzer of reduction reaction, suitable has metal such as Raney nickel or noble metal catalyst as choosing palladium or platinum or the palladium hydroxide on carrier wantonly.Substitute hydrogen, for example also can use ammonium formiate, tetrahydrobenzene or hydrazine in known manner.Also can use reductive agent such as tin protochloride (II) or titanium chloride (III), as composite metal hydride, the optional heavy metallic salt that exists.Also can use iron as reductive agent.Acid as acetate or ammonium chloride in the presence of, choose interpolation solvent such as water, methyl alcohol, iron/ammoniacal liquor etc. wantonly, react.At the reaction times overtime, can carry out amino acylations by this variation pattern.
If wish amino is carried out alkylation, then can for example use alkyl halide according to normally used method, perhaps pass through in the presence of for example triphenylphosphine and azodicarboxylate, to react with alcohol according to the method for Mitsonubo, carry out alkylation.The also available aldehydes or ketones of amine carries out standard reductive alkylation, wherein in the presence of reductive agent such as sodium cyanoborohydride, in suitable inert solvent such as ethanol, under the boiling temperature of 0 ℃-solvent, carries out described reaction.If initial by primary amino, then react to optional order with two kinds of different carbonyl compound, obtain mixed derivative (reference: people such as Verardo, Synthesis (1993), 121 thus; Synthesis (1991), 447; Kawaguchi, Synthesis (1985), 701; People such as Mocovic, Synthesis (1991), 1043).Advantageously at first in solvent the reaction by aldehyde and amine form Schiff alkali, wherein solvent for example is ethanol or methyl alcohol, and optional assistant agent such as the glacial acetic acid of adding, and only adds reductive agent such as sodium cyanoborohydride then.
The hydrogenation of alkenyl or alkynyl can for example be undertaken by catalytic activation hydrogenation according to usual method in the molecule.For catalyzer, can use heavy metal as choosing palladium or the platinum on carrier, perhaps Raney nickel wantonly.Solvent can be pure as ethanol.The temperature of reaction is the boiling point of 0 ℃-solvent, and pressure is up to 20bar, but preferably under room temperature and normal pressure.By using for example Lindlar catalyzer of catalyzer, can with triple bond partly hydrogenation be pair keys, preferably prepare the Z-form thus.The palladium that this hydrogenation preferably is used in the pyridine as solvent on the lime carbonate carries out as catalyzer.According to identical method, use for example according to people such as R.M.Moriatry, Synth.Comm.17,703,1987 diimines that make reduce, and can prepare the two keys of Z-by triple bond.
Amino acylations can be according to the Schotten-Baumann method in the aqueous solution of weakly alkaline pH; carry out with for example carboxylic acid halides or acid anhydrides according to common mode; wherein optional alkali such as the dimethyl aminopyridine of existing; solvent for example is methylene dichloride, tetrahydrofuran (THF) or pyridine, perhaps in glacial acetic acid by with the reaction of acid anhydrides.
The reduction of ketone group can be carried out according to methods known in the art.Thus,, in solvent such as methyl alcohol or Virahol, remove amide group or ester group, optionally ketone group is reduced to alcohol with composite metal hydride such as sodium borohydride.According to the Clemmensen method, in hydrochloric acid, use zinc, perhaps for example in trifluoroacetic acid, use silane, ketone group can be reduced to methylene radical.
For example chlorine, bromine, iodine or azido-also can for example carry out with diazonium salt according to the Sandmeyer method to introduce halogen by amino, this diazonium salt is by the reaction intermediate formation of nitrile and cuprous chloride (I) or cuprous bromide (I), wherein there is corresponding acid, example hydrochloric acid or Hydrogen bromide are perhaps used potassiumiodide.
If use organic nitrite,, in solvent such as dimethyl formamide, can introduce halogen by for example adding methylene iodide or four boron methane.Amino removes and can realize by the following method: with organic nitrite reaction, perhaps carry out diazotization and reductibility boiling diazonium salt with for example phosphoric acid in tetrahydrofuran (THF), the optional Red copper oxide (I) that adds.
The introducing of fluorine can for example following realization: by the Balz-Schiemann reaction of diazonium tetrafluoroborate, perhaps according to J.Fluor.Chem.76,1996,59-62, in the presence of the HF-pyridine, carry out diazotization, carry out boiling when having fluoride sources such as tetrabutyl ammonium fluoride optional subsequently.
The introducing of azido-can after the diazotization by realizing with the reaction of sodiumazide under the room temperature.
Ether cleavage can be carried out according to known method in the document.In the case, realize optionally splitting in several groups that also can in molecule, exist.At this moment, for example in solvent such as methylene dichloride, in-100 ℃ to solvent boiling point, preferred-78 ℃ temperature, handle ether with boron tribromide.But, also can in solvent such as dimethyl formamide, carry out ether cleavage with the sulfo-sodium methylate.Temperature of reaction can be between the temperature of room temperature-solvent boiling point, preferably at 150 ℃.
The introducing of thiazolinyl can be carried out with corresponding vinyl compound under the Heck reaction conditions.When introducing ethynyl, use the Songashira reaction.
For leavings group R 2 ', suitable have halogen such as fluorine, chlorine, bromine, iodine or O-methylsulfonic acid base, O-toluenesulphonic acids base, O-trifluoromethanesulfonic acid base or an O-nonaflate.Under the catalysis of transition metal composite, according to known method in the document of this area, exist under the common catalysis of alkali and optional salt such as cuprous iodide (I) or lithium chloride optional, introduce the nucleophilic substitution reaction of ethynyl or vinyl, wherein said transition metal for example is Pd (O), as tetrakis triphenylphosphine palladium, and perhaps Pd (2+), as two (trimethylphenyl phosphine) palladium chloride, nickel (II) or nickel (O).
As nucleophilic reagent, suitable for example have vinyl or acetylene compound, organo-tin compound or an organic zinc compound.Reaction can in hydrocarbon such as toluene or ether such as tetrahydrofuran (THF), glycol dimethyl ether or Anaesthetie Ether, be carried out described reaction in polar solvent such as dimethyl formamide, N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, acetonitrile.As alkali, suitable have mineral alkali such as basic metal or alkaline earth metal hydroxides or supercarbonate, carbonate, phosphoric acid salt, perhaps organic bases such as ring-type, non-annularity and aromatic amine, as pyridine, triethylamine, DBU and Huenig alkali, in many cases, also can be such as the alkali of diethylamide and piperidines simultaneously as solvent.Exert pressure and help the carrying out that react.
If introduce the trimethyl silyl ethynyl, can be in solvent such as tetrahydrofuran (THF), methylene dichloride or acetonitrile, under the boiling temperature of 0 ℃-solvent, by introducing trimethyl silyl with the reaction of fluorochemical such as Potassium monofluoride or tetrabutyl ammonium fluoride.
Yet, also can introduce thiazolinyl by olefination such as Peterson olefination, Wittig reaction or Wittig-Horner reaction.For this purpose, make aldehyde and the anionic reactive that makes in advance in solvent, as the microcosmic salt or the phosphonic acid ester of corresponding replacement, solvent for example is toluene, tetrahydrofuran (THF), diethyl ether or glycol dimethyl ether.As alkali, suitable have alkalimetal hydride, alkali metal amide, alkali metal alcoholates such as potassium tert.-butoxide, basic metal and alkaline earth metal carbonate or oxyhydroxide, wherein there are phase-transfer catalyst such as crown ether, or organic bases such as triethylamine, diisopropyl ethyl amine or diazabicylo undecane, and optional salt such as the lithiumbromide of existing.
Can isomer mixture be separated into enantiomorph or E/Z isomer according to method such as crystallization process, chromatography or the salt formation method of routine use.
The preparation of salt can be carried out according to ordinary method, and the solution of formula I compound and equivalent or excessive alkali or acid are mixed, and these alkali or acid can be chosen wantonly in solution, then sediment separate out or according to the ordinary method treatment soln.
Though do not describe the preparation of intermediate compound, can use compound known or according to the method preparation that is similar to known compound, perhaps according to method preparation described here.
The intermediate compound of having described is particularly suitable for preparation according to benzoic amide of the present invention.
Specially suitable is intermediate compound and isomer and the salt of general formula I I:
Figure A0180860000211
Wherein: R 2And R 3Represent hydrogen or radicals X R 11, X represents C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Representative is optional by C 1-6Phenyl and pyridyl that alkoxyl group replaces are at this R 2And R 3Represent hydrogen, but be not hydrogen simultaneously.
These intermediate compounds are also included within the scope of the present invention.
Intermediate product itself is that part is active, therefore also can be used for preparing the medicine for the treatment of following disease: tumour, psoriasis, sacroiliitis such as rheumatoid arthritis, vascular tumor, hemangiofibroma, ophthalmic such as diabetic retinopathy, neovascular glaucoma, ephrosis such as glomerulonephritis, diabetic nephropathy, pernicious renal necrosis, embolic microangiopathy syndromes, graft rejection reaction and glomerulopathy, fibrotic conditions such as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis, and the damage of nervous tissue.
Following examples are the explanations to the preparation The compounds of this invention, but scope of the present invention never only limits to these embodiment.
Embodiment 1.0 preparation (N-4-chloro-phenyl-)-2-(4-pyridyl ethyl) benzoic amides
The 2-of 105mg (4-pyridyl ethyl) methyl benzoate mixes with the 4-chloroaniline of 56mg in 7.5ml toluene, is cooled to 4 ℃, mixes with the trimethyl aluminium (2M hexane solution) of 0.22ml in the environment of argon gas and no moisture then.Heated mixt is 2 hours under 120 ℃ bath temperature.After the cooling, mix, and use twice of the ethyl acetate extraction of 25ml respectively with the dilute solution of sodium bicarbonate of 30ml.Organic phase washes with water, and drying is filtered, then evaporation concentration.Residue separates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, wherein uses ethyl acetate: hexanaphthene=1: 1 is as eluent.Obtain (N-4-chloro-phenyl-)-2-(4-pyridyl ethyl) benzoic amide of oily 133mg (theoretical value 89%).Be similar to the following compound of embodiment 1.0 preparations:
Figure A0180860000231
Figure A0180860000232
Figure A0180860000261
Figure A0180860000271
Figure A0180860000281
Embodiment 2.0 preparation N-4-chloro-phenyl--3-(2-pyridyl vinyl) benzoic amides
N-4-chloro-phenyl--3-of 179mg (2-pyridyl ethynyl) benzoic amide mixes with the palladium (5%) of 20mg on lime carbonate in the 7ml pyridine, hydrogenation 1.5 hours under normal hydrogen pressure and room temperature then.Behind suction filtration catalyzer on the diatomite, evaporation concentration filtrate.Residue separates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, wherein uses ethyl acetate: hexane=1: 1 is as eluent.Obtain 123mg (theoretical value 68%) buttery (Z)-N-4-chloro-phenyl--3-(2-pyridyl vinyl) benzoic amide.
Be similar to the following compound of embodiment 2.0 preparations:
Figure A0180860000301
Embodiment 3.0 preparation (E)-N-4-chloro-phenyl--3-(2-pyridyl vinyl) benzoic amides
(Z)-N-4-chloro-phenyl--3-of 120mg (2-pyridyl vinyl) benzoic amide mixes with iodine in toluene, refluxes then 7 hours.After the evaporation concentration, residue separates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, wherein uses ethyl acetate: hexane=1: 1 is as eluent.Obtain (E)-N-4-chloro-phenyl--3-(2-pyridyl vinyl) benzoic amide of 60mg (theoretical value 50%), its fusing point is 212.7 ℃.
Similarly prepare following compound:
Figure A0180860000302
Figure A0180860000311
Embodiment 4.0 preparation N-(4-chloro-phenyl-)-2-[3-(4-hydroxy phenyl) propyl group] benzoic amide
The N-of 90mg (4-chloro-phenyl-)-2-[3-(4-p-methoxy-phenyl) propyl group] benzoic amide dropwise mixes with the boron tribromide of 1.2ml under-78 ℃ in the methylene dichloride of 8ml.After interpolation finishes, at room temperature stir and spend the night.Mix with water then, vacuum distilling goes out methylene dichloride, uses ethyl acetate jolting water outlet then.Ethyl acetate is carried out evaporation concentration mutually, on silica gel residue is carried out chromatographic separation then, wherein uses hexane: ethyl acetate=8: 2 is as eluent.Obtain N-(4-chloro-phenyl-)-2-[3-(4-hydroxy phenyl) propyl group of 24mg (theoretical value 28%)] benzoic amide.
Prepare following compound similarly:
Embodiment 5.0 preparation N-(4-chloro-phenyl-)-3-(4-methoxyl-styrene) salicylamides
With the 4-methoxyl group-2 of 904mg '-hydroxy styrenes is introduced in the toluene of 40ml, mixes with the boron trichloride solution (1mol hexane solution) of 4ml down at 4 ℃ then.At room temperature stirred 1 hour, and mixed, heated 1.5 hours down at 120 ℃ then with the 4-chloro-phenyl-isocyanic ester of 614mg.Then with the methanol mixed of 5ml, evaporation concentration then.Residue is to carry out chromatographic separation twice at silica gel, uses ethyl acetate for the first time: hexane=1: 1 wash-out, and use toluene for the second time: ethyl acetate=100: 3.5 wash-outs.Obtain 150mg (theoretical value 10%) buttery N-(4-chloro-phenyl-)-3-(4-methoxyl-styrene) salicylamide.
Prepare following compound similarly:
Embodiment ????R 3 Fusing point (℃)
????5.1 ????3-MeO-Ph ????116.3
????5.2 ????3-MeO-Ph-CH 2
????5.3 ????4-MeO-Ph-CH 2 ????163.6
The preparation intermediate compound
Embodiment Z-5.0 prepare 4-methoxyl group-2 '-hydroxy styrenes
2.44g salicylic aldehyde mixes with 4-methoxyl group-benzyl triphenyl phosphonium chloride phosphine of 12.5g earlier in 200ml toluene.Add the potassium tert.-butoxide of 2.24g then, and use ice-cooled simultaneously.Under this temperature, stirred 1 hour, at room temperature stirred then 3.5 hours.After mixing with 100ml water and carrying out acidifying, with the ethyl acetate extraction of 50ml with 1N hydrochloric acid.The organic phase of collecting is washed with saturated sodium-chloride water solution, and drying is filtered and evaporation concentration.Residue separates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, wherein uses ethyl acetate: hexane=2: 8 is as eluent.Obtain the 4-methoxyl group-2 of 3.1g (theoretical value 68%) '-hydroxy styrenes.
Prepare following compound similarly:
Embodiment ????R 3 Fusing point (℃)
????Z-5.1 ????3-MeO-Ph Oily
????Z-5.2 ????3-MeO-Ph-CH 2 Oily
????Z-5.3 ????4-MeO-Ph-CH 2 Oily
Embodiment 6.0 preparation N-(4-chloro-phenyl-)-3-(4-anisole ethyl) salicylamides
The 4-methoxyl group-2 of 813mg '-hydroxyl-1, the 2-diphenylethane is similar to embodiment Z-5.0 and reacts.The residue that obtains after handling as mentioned above separates in the enterprising circumstances in which people get things ready for a trip of silica gel spectrum, wherein uses ethyl acetate: hexane=1: 1 is as eluent, the corresponding cut of evaporation concentration, and stir with ethyl acetate/hexane, obtain the material of crystallized form.Obtain N-(4-chloro-phenyl-)-3-(4-anisole ethyl) salicylamide of 375mg (theoretical value 27.6%), its fusing point is 141 ℃.
Prepare following compound similarly:
Embodiment ????R 3 Fusing point (℃)
????6.1 ????3-MeO-Ph ????130.2
????6.2 ????3-MeO-Ph-CH 2 Oily
????6.3 ????4-MeO-Ph-CH 2 ????158
The preparation intermediate compound
Embodiment Z-6.0 prepare 4-methoxyl group-2 '-hydroxyl-1, the 2-diphenylethane
The 4-methoxyl group-2 of 905mg '-hydroxy styrenes mixes with the palladium (10) of 1.3g on carbon in the ethanol of 50ml, depresses hydrogenation 70 minutes in room temperature and normal hydrogen then.After suction filtration goes out catalyzer and evaporation concentration, obtain the 4-methoxyl group-2 of 880mg '-hydroxyl-1, the 2-diphenylethane.
Prepare following compound similarly:
Figure A0180860000351
Embodiment ????R 3 Fusing point (℃)
????Z-6.1 ????3-MeO-Ph Oily
????Z-6.2 ????3-MeO-Ph-CH 2 Oily
????Z-6.3 ????4-MeO-Ph-CH 2
Embodiment 7.0 preparation intermediate products
Following examples are explanation preparations according to intermediate product of the present invention, and these intermediate products are particularly suitable for preparation according to compound of Formula I of the present invention, but are not limited only to these embodiment.Method A prepares 2-(4-pyridyl vinyl) methyl benzoate
2.10g 2-iodo-benzoic acid methyl esters and the mixture of 4-vinylpridine in the 24ml dimethyl formamide of 0.97g mix in argon gas with the tri-o-tolyl phosphine of the triethylamine of 1.04g and the acid chloride of 40mg (II) and 24mg, then in the glass pressure container in 100 ℃ the heating 5 hours.After vacuum-evaporation concentrated, residue separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, wherein uses hexane: ethyl acetate=1: 1 is as eluent.Obtain 2-(the 4-pyridyl vinyl) methyl benzoate of 1.8g (theoretical value 94%).Method B prepares 2-(4-pyridyl ethynyl) methyl benzoate
2.10g 2-iodo-benzoic acid methyl esters in the dimethyl formamide of 25ml, under argon gas, mix with the triethylamine of 2.94g, two (triphenylphosphine) Palladous chloride (II) of 179mg, the cuprous iodide (I) of 111mg and the 4-ethynyl pyridine of 900mg, then in the glass pressure container under 80 ℃ bath temperature the heating 3.5 hours.After vacuum-evaporation concentrated, residue separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, wherein uses hexane: acetone=1: 1 is as eluent.Obtain 2-(the 4-pyridyl ethynyl) methyl benzoate of 1.08g (theoretical value 45%).Method C prepares 2-(4-pyridyl ethyl) methyl benzoate
The 2-of 237mg (4-pyridyl ethynyl) methyl benzoate mixes with the palladium (10%) of 200mg on charcoal in the ethanol of 30ml, hydrogenation 20 minutes under normal hydrogen pressure and room temperature then.Suction filtration goes out catalyzer on diatomite, then evaporation concentration filtrate.Obtain 2-(the 4-pyridyl ethyl) methyl benzoate of 220mg.
Substitute acetylene compound, also can use corresponding vinyl compound.Method D
Method according to describing among the embodiment 2.0 also can be converted into the Z compound with corresponding ester.Method E
Method according to describing among the embodiment 3.0 when ester, also can make the E compound by the corresponding Z compound.Method F
According to the method for describing among the method B, also can make 2-trimethyl silyl acetylenylbenzene methyl-formiate by 2-iodo ethyl benzoate and ethynyl trimethyl silane, yield is 83%.Method G
The 2-trimethyl silyl acetylenylbenzene methyl-formiate of 464mg mixes with the tetrabutyl ammonium fluoride (1M tetrahydrofuran solution) of 2.75ml in the 15ml anhydrous methylene chloride, at room temperature stirs then 2.5 hours.After the weak ammonia washing, dry organic phase is filtered and evaporation concentration.Not further pure system promptly is used for next step reaction.Method H
Make the 3-iodoanisole reaction of the 2-acetylenylbenzene methyl-formiate of 440mg and 1.94g according to method B, using ethyl acetate on the silica gel: hexane=2.8 as eluent carry out making after the pure system of column chromatography the 2-ethoxycarbonyl methyl-3 of 680mg (theoretical value 55.3%) '-the methoxyl group dibenzenyl.Prepare following compound similarly:
Figure A0180860000382
Following application examples is used to illustrate physiological action and the purposes according to compound of the present invention, but scope of the present invention is not limited among these embodiment.Test solution materials solution materials solution A: 3mM ATP, in water, pH7.0 (70 ℃) material solution B:g-33P-ATP 1mCi/100 μ l material solution C:poly-(Glu4Tyr) mg/ml, the dilution DTT of solution substrate solution: 100mM in water, the 10mM Manganous chloride tetrahydrate, 100mM magnesium chloride enzyme solution: 120mM Tris/HCl, pH7.5,10 μ M vanadium oxide sodium application examples 1 when compound according to the present invention exists to the restraining effect of KDR-and FLT-1 kinase activity
In the titer plate that comes to a point downwards (not having protein binding), the inhibitor solution of substrate mixture (the substrate solvent of poly-(Glu4Tyr) the material solution C+1.21ml of g-33P-ATP (the material solution B of about 2.5 μ l)+30 μ l of the ATP material solution A+25 μ Ci of 10 μ l volumes), 10 μ l that adds 10 μ l is (corresponding to the material of diluent, 3%DMSO is in the substrate solvent, in contrast) and the enzyme solution of 10 μ l (the proenzyme material solution of 11.25 μ g (KDR or FLT-1 kinases) is diluted in the 1.25ml enzyme solution under 4 ℃).Thorough mixing, incubation 10 minutes at room temperature then.(EDTA of 250mM pH7.0), mixes, and the solution with 10 μ l is transferred on the P81 phosphorylated cotton strainer then then to add stop bath.With the phosphoric acid washing of 0.1M repeatedly.Dry filter paper with the Meltilex coating, is measured in the microbeta counter then.
Determine the IC50 value by inhibitor concentration, it is after removing blank reading (reaction of EDTA terminated) phosphoric acid to be mixed inhibition to be uncorporated 50% needed inhibitor concentration.
The result of kinase inhibitory activity IC50 (μ M) is shown in the following table.
Embodiment ????VEGFR?I(FLT) ????VEGFR?II(KDR)
????1.60 ????2 ????0.5
????1.31 ????0.2 ????0.4
????1.89 ????2 ????0.3
????1.54 ????0.05 ????0.5
????1.57 ????0.2 ????0.2
????1.64 ????0.2 ????0.3
????1.67 ????KH ????5
????1.1 ????0.2 ????0.2
KH=does not suppress

Claims (11)

1, the compound of general formula I and isomer thereof and salt: Wherein: A represents group=NR 7, W represents oxygen, sulphur, two hydrogen atoms or group=NR 8, Z represents a key, group=NR 10Perhaps=N-, straight chain or side chain C 1-12Alkyl or
Following group:
Figure A0180860000022
M, n and o represent 0-3, R a, R b, R c, R d, R e, R fRepresent hydrogen, fluorine, C respectively independently 1-4Alkyl or group
=NR 10, and/or R aAnd/or R bWith R cAnd/or R dForm a key or R cWith R eAnd/or
R fForm key, perhaps a radicals R a-R fIn maximum two can closure have maximum 3 carbon
The bridge of atom forms R respectively 1Perhaps form R 7, R 1Representative is chosen wantonly in one or more position by halogen or C 1-6The straight chain that alkyl replaces or
Person's side chain C 1-6Alkyl, C 2-12Thiazolinyl or C 3-12Alkynyl, perhaps representative is chosen wantonly at one
Perhaps a plurality of positions are by halogen or C 1-6The C that alkyl replaces 3-10Cycloalkyl or C 3-10
Cycloalkenyl group, perhaps representative be unsubstituted or choose wantonly in one or more position by halogen,
C 1-6Alkyl, C 1-6Alkoxyl group or replaced by halogen in one or more position
C 1-6Alkyl or C 1-6Aryl or heteroaryl that alkoxyl group replaces, R 2And R 3Represent hydrogen, OH group or radicals X R 11, X represents C 2-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Represent monocyclic aryl, aryl bicyclic or heteroaryl, they can be unsubstituted or choose wantonly one
Individual or a plurality of positions are by halogen, C 1-6Alkyl, C 1-6Alkoxyl group or hydroxyl replace, R 4, R 5And R 6Represent hydrogen, halogen or do not replace or in one or more position by halogen
The plain C that replaces 1-6Alkoxyl group, C 1-6Alkyl or C 1-6Carboxyalkyl, perhaps R 4And R 5
Form following group together:
Figure A0180860000031
R 7Represent hydrogen or C 1-6Alkyl or with Z in R a-R fFormation contains maximum 3 annular atomses
Bridge or form R 1, R 8And R 10Represent hydrogen or C 1-6Alkyl, wherein R 2And R 3Represent hydrogen, but different times table hydrogen,
If R 2Represent the OH group, then R 3Do not represent hydrogen, and if R 3Represent the OH base
Group, then R 2Do not represent hydrogen, and R 1It must not thiazole.
2, compound of Formula I as claimed in claim 1, wherein: A represents group=NR 7, W represents oxygen, sulphur or two hydrogen atoms, and Z represents a key, group=NR 10Perhaps straight chain or side chain C 1-12Alkyl R 1Representative is chosen wantonly in one or more position by halogen or C 1-6The straight chain that alkyl replaces or
Person's side chain C 1-6Alkyl, perhaps representative choose wantonly in one or more position by halogen or
C 1-6The C that alkyl replaces 3-10Cycloalkyl, perhaps the representative be unsubstituted or choose wantonly one or
The a plurality of positions of person are by halogen, C 1-6Alkyl, C 1-6Alkoxyl group or at one or many
The C that individual position is replaced by halogen 1-6Alkyl or C 1-6Phenyl, pyridine that alkoxyl group replaces
Base, naphthyl, quinolyl, isoquinolyl, indanyl, 1,2,3,4-tetralin base,
Indyl, thienyl, indazolyl or benzothiazolyl, R 2And R 3Represent hydrogen, OH group or radicals X R 11, X represents C 2-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Representative does not replace or chooses wantonly in one or more position by halogen, C 1-6Alkoxyl group or
Phenyl, pyrimidyl or pyridyl that person's hydroxyl replaces, R 4, R 5, R 6And R 7Represent hydrogen, R 8And R 10Represent hydrogen or C 1-6Alkyl, wherein R 2And R 3Represent hydrogen, but different times table hydrogen,
If R 2Represent the OH group, then R 3Do not represent hydrogen, and if R 3Represent the OH base
Group, then R 2Do not represent hydrogen.
3, compound of Formula I as claimed in claim 1 or 2 and isomer thereof and salt, wherein: A represents group=NR 7, W represents oxygen or one or two hydrogen atom, and Z represents a key, group=NR 10Perhaps straight chain or side chain C 1-12Alkyl R 1Represent straight chain or side chain C 1-6Alkyl, perhaps representative is chosen wantonly in one or more position
By halogen or C 1-6The C that alkyl replaces 3-10Cycloalkyl, perhaps representative is unsubstituted or appoints
Be selected in one or more position by halogen, C 1-6Alkyl, C 1-6Alkoxyl group or
The C that one or more position is replaced by halogen 1-6Alkyl or C 1-6Alkoxyl group replaces
Phenyl, pyridyl, naphthyl, quinolyl, isoquinolyl, indenyl, 1,2,3,4-four
Hydrogenation naphthyl, indyl, thienyl, indazolyl or benzothiazolyl, R 2And R 3Represent hydrogen, OH group or radicals X R 11, X represents C 2-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Representative does not replace or chooses wantonly in one or more position by halogen, C 1-6Alkoxyl group or
Phenyl, pyrimidyl or pyridyl that person's hydroxyl replaces, R 4, R 5, R 6And R 7Represent hydrogen, R 8And R 10Represent hydrogen or C 1-6Alkyl, wherein R 2And R 3Represent hydrogen, but different times table hydrogen,
If R 2Represent the OH group, then R 3Do not represent hydrogen, and if R 3Represent the OH base
Group, then R 2Do not represent hydrogen.
4, be used for the treatment of application in the medicine of following disease as the described compound of Formula I of one of claim 1-3 in preparation: tumour, psoriasis, sacroiliitis such as rheumatoid arthritis, vascular tumor, hemangiofibroma, ophthalmic such as diabetic retinopathy, neovascular glaucoma, ephrosis such as glomerulonephritis, diabetic nephropathy, pernicious renal necrosis, embolic microangiopathy syndromes, graft rejection reaction and glomerulopathy, fibrotic conditions such as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis, and the damage of nervous tissue.
5, a kind of medicine, it comprises at least a as the described compound of one of claim 1-3.
6, medicine as claimed in claim 5, it is to be used for the treatment of tumour, psoriasis, sacroiliitis such as rheumatoid arthritis, vascular tumor, hemangiofibroma, ophthalmic such as diabetic retinopathy, neovascular glaucoma, ephrosis such as glomerulonephritis, diabetic nephropathy, pernicious renal necrosis, embolic microangiopathy syndromes, graft rejection reaction and glomerulopathy, fibrotic conditions such as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis, and the damage of nervous tissue.
7, a kind of pharmaceutical preparation, it comprises as described compound of one of claim 1-3 and carrier.
8, as of the application of the described compound of Formula I of one of claim 1-3 as the inhibitor of Tyrosylprotein kinase KDR and FLT.
9, as of the application of the described compound of Formula I of one of claim 1-3 at the pharmaceutical preparation that is used for enteron aisle, parenteral route and oral administration.
10, general formula I I intermediate compound and the isomer and the salt of the intermediate product of the compound of conduct preparation general formula I:
Figure A0180860000061
Wherein: R 2And R 3Represent hydrogen or radicals X R 11, X represents C 1-6Alkyl, C 2-6Thiazolinyl or C 2-6Alkynyl, R 11Representative is optional by C 1-6Phenyl and pyridyl that alkoxyl group replaces are at this R 2And R 3Represent hydrogen,
But be not hydrogen simultaneously.
11, general formula I I compound as claimed in claim 10 is used for the treatment of application in the medicine of following disease in preparation: tumour, psoriasis, sacroiliitis such as rheumatoid arthritis, vascular tumor, hemangiofibroma, ophthalmic such as diabetic retinopathy, neovascular glaucoma, ephrosis such as glomerulonephritis, diabetic nephropathy, pernicious renal necrosis, embolic microangiopathy syndromes, graft rejection reaction and glomerulopathy, fibrotic conditions such as liver cirrhosis, mesangial cell proliferative disease and arteriosclerosis, and the damage of nervous tissue.
CNB018086004A 2000-04-25 2001-04-24 Substituted benzoic acid amides and use for inhibition of angiogenesis thereof Expired - Fee Related CN1285578C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10021246.8 2000-04-25
DE10021246A DE10021246A1 (en) 2000-04-25 2000-04-25 New N-substituted benzamide derivatives are tyrosine kinase KDR and FLT inhibitors useful e.g. for treating tumors, psoriasis, rheumatoid arthritis, diabetic retinopathy or liver sclerosis

Publications (2)

Publication Number Publication Date
CN1426396A true CN1426396A (en) 2003-06-25
CN1285578C CN1285578C (en) 2006-11-22

Family

ID=7640467

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB018086004A Expired - Fee Related CN1285578C (en) 2000-04-25 2001-04-24 Substituted benzoic acid amides and use for inhibition of angiogenesis thereof

Country Status (28)

Country Link
US (1) US20110009447A1 (en)
EP (1) EP1280776B1 (en)
JP (1) JP2004512259A (en)
KR (1) KR100904101B1 (en)
CN (1) CN1285578C (en)
AT (1) ATE446288T1 (en)
AU (2) AU5227201A (en)
BG (1) BG107212A (en)
BR (1) BR0110246A (en)
CA (1) CA2406392C (en)
CZ (1) CZ20023545A3 (en)
DE (2) DE10021246A1 (en)
EE (1) EE200200609A (en)
ES (1) ES2334433T3 (en)
HK (1) HK1056559A1 (en)
HR (1) HRP20020933A2 (en)
HU (1) HUP0300920A1 (en)
IL (1) IL152292A0 (en)
MX (1) MXPA02010559A (en)
NO (1) NO325445B1 (en)
NZ (1) NZ521681A (en)
PL (1) PL358457A1 (en)
RU (1) RU2353618C2 (en)
SK (1) SK15222002A3 (en)
UA (1) UA82980C2 (en)
WO (1) WO2001081311A1 (en)
YU (1) YU71102A (en)
ZA (1) ZA200209494B (en)

Families Citing this family (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105682B2 (en) 2001-01-12 2006-09-12 Amgen Inc. Substituted amine derivatives and methods of use
US6995162B2 (en) 2001-01-12 2006-02-07 Amgen Inc. Substituted alkylamine derivatives and methods of use
US20030134836A1 (en) 2001-01-12 2003-07-17 Amgen Inc. Substituted arylamine derivatives and methods of use
US6878714B2 (en) 2001-01-12 2005-04-12 Amgen Inc. Substituted alkylamine derivatives and methods of use
US7102009B2 (en) 2001-01-12 2006-09-05 Amgen Inc. Substituted amine derivatives and methods of use
TWI243164B (en) 2001-02-13 2005-11-11 Aventis Pharma Gmbh Acylated indanyl amines and their use as pharmaceuticals
US7307088B2 (en) 2002-07-09 2007-12-11 Amgen Inc. Substituted anthranilic amide derivatives and methods of use
SG153714A1 (en) 2003-08-06 2009-07-29 Senomyx Inc T1r hetero-oligomeric taste receptors, cell lines that express said receptors, and taste compounds
UA89035C2 (en) 2003-12-03 2009-12-25 Лео Фарма А/С Hydroxamic acid esters and pharmaceutical use thereof
TW200529812A (en) * 2003-12-26 2005-09-16 Chugai Pharmaceutical Co Ltd Benzamide derivatives
DE102004009238A1 (en) * 2004-02-26 2005-09-08 Merck Patent Gmbh New aryl amide compounds are kinase inhibitors useful for the treatment and/or prophylaxis of e.g. tumors, psoriasis, rheumatoid arthritis, contact dermatitis, inflammations, endometriosis, scar and benign prostatic hyperplasia
US8247556B2 (en) 2005-10-21 2012-08-21 Amgen Inc. Method for preparing 6-substituted-7-aza-indoles
ES2761180T3 (en) 2005-12-23 2020-05-19 Ariad Pharma Inc Bicyclic heteroaryl compounds
KR101387563B1 (en) 2006-04-21 2014-04-25 세노믹스, 인코포레이티드 Comestible compositions comprising high potency savory flavorants, and processes for producing them
EP2024342A2 (en) 2006-05-01 2009-02-18 Pfizer Products Incorporated Substituted 2-amino-fused heterocyclic compounds
JP5273037B2 (en) 2006-05-08 2013-08-28 アリアド・ファーマシューティカルズ・インコーポレイテッド Acetylene heteroaryl compounds
CN103467385B (en) 2006-05-08 2016-03-09 阿里亚德医药股份有限公司 Bicyclic heteroaryl compounds
BRPI0718895A2 (en) * 2006-11-16 2013-12-10 Allergan Inc SULFOXIMIN COMPOUND AND USE OF SUCH COMPOUND
AU2007333925B2 (en) 2006-12-15 2013-10-31 Nantbio, Inc. Triazine derivatives and their therapeutical applications
EP2076124A4 (en) 2007-04-20 2011-08-03 Acucela Inc Styrenyl derivative compounds for treating ophthalmic diseases and disorders
TWI490214B (en) * 2008-05-30 2015-07-01 艾德克 上野股份有限公司 Benzene or thiophene derivative and use thereof as vap-1 inhibitor
AU2009287152B2 (en) 2008-08-27 2014-09-25 Leo Pharma A/S Pyridine derivatives as VEGFR-2 receptor and protein tyrosine kinase inhibitors
US8846664B2 (en) 2008-11-12 2014-09-30 Ariad Pharmaceuticals, Inc. Pyrazinopyrazines and derivatives as kinase inhibitors
EP2379076B1 (en) 2008-12-23 2014-11-12 The Trustees of Columbia University in the City of New York Phosphodiesterase inhibitors and uses thereof
JP5785940B2 (en) 2009-06-09 2015-09-30 アブラクシス バイオサイエンス， エルエルシー Triazine derivatives and their therapeutic applications
JP2012529517A (en) 2009-06-09 2012-11-22 アブラクシス バイオサイエンス リミテッド ライアビリティー カンパニー Benzyl-substituted triazine derivatives and their therapeutic applications
TW201103904A (en) 2009-06-11 2011-02-01 Hoffmann La Roche Janus kinase inhibitor compounds and methods
WO2012080284A2 (en) 2010-12-17 2012-06-21 F. Hoffmann-La Roche Ag Substituted 6,6-fused nitrogenous heterocyclic compounds and uses thereof
CA3022250A1 (en) 2012-12-12 2014-06-12 Ariad Pharmaceuticals, Inc. Crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-n-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride
KR20160110357A (en) 2013-11-15 2016-09-21 더 위스타 인스티튜트 오브 아나토미 앤드 바이올로지 E b n a 1 inhibitors and their method of use
US10442763B2 (en) 2015-05-14 2019-10-15 The Wistar Institute Of Anatomy And Biology EBNA1 inhibitors and methods using same
CN106740403A (en) * 2017-03-21 2017-05-31 西北工业大学 A kind of liquid nitrogen power output system and hybrid power cold chain transportation car
US11242338B2 (en) 2018-05-17 2022-02-08 The Wistar Institute EBNA1 inhibitor crystalline forms, and methods of preparing and using same

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1643265C3 (en) * 1967-12-22 1978-08-31 C.H. Boehringer Sohn, 6507 Ingelheim Nuclear-substituted 2-aminomethylbenzhydrols, processes for their preparation and pharmaceuticals based on these compounds
JPH02218654A (en) * 1988-10-12 1990-08-31 Ono Pharmaceut Co Ltd Benzoic acid derivative, production thereof and drug containing the same
DE19648793A1 (en) * 1996-11-26 1998-05-28 Basf Ag New benzamides and their application
US5863455A (en) * 1997-07-14 1999-01-26 Abb Power T&D Company Inc. Colloidal insulating and cooling fluid
JP3013989B2 (en) * 1998-03-26 2000-02-28 日本たばこ産業株式会社 Amide derivatives and nociceptin antagonists
WO2000002871A1 (en) * 1998-07-10 2000-01-20 Merck & Co., Inc. Novel angiogenesis inhibitors
EP1109555A4 (en) * 1998-08-31 2001-11-21 Merck & Co Inc Novel angiogenesis inhibitors
BR9915139A (en) * 1998-11-06 2001-08-07 Basf Ag Method of inhibiting vascular hyperpermeability, and of inhibiting a physiological process or state in an individual
GB9824579D0 (en) * 1998-11-10 1999-01-06 Novartis Ag Organic compounds
HN2001000008A (en) * 2000-01-21 2003-12-11 Inc Agouron Pharmaceuticals AMIDA COMPOSITE AND PHARMACEUTICAL COMPOSITIONS TO INHIBIT PROTEINKINASES, AND THE INSTRUCTIONS FOR USE

Also Published As

Publication number Publication date
EE200200609A (en) 2004-04-15
JP2004512259A (en) 2004-04-22
CN1285578C (en) 2006-11-22
SK15222002A3 (en) 2003-06-03
HRP20020933A2 (en) 2005-02-28
HK1056559A1 (en) 2004-02-20
UA82980C2 (en) 2008-06-10
BG107212A (en) 2003-05-30
DE50115189D1 (en) 2009-12-03
IL152292A0 (en) 2003-05-29
ZA200209494B (en) 2004-07-14
NO325445B1 (en) 2008-05-05
DE10021246A1 (en) 2001-10-31
NO20025102D0 (en) 2002-10-24
NZ521681A (en) 2006-03-31
MXPA02010559A (en) 2003-03-10
AU2001252272B2 (en) 2007-03-29
EP1280776A1 (en) 2003-02-05
HUP0300920A1 (en) 2003-07-28
YU71102A (en) 2006-03-03
US20110009447A1 (en) 2011-01-13
PL358457A1 (en) 2004-08-09
NO20025102L (en) 2002-12-17
CZ20023545A3 (en) 2003-02-12
BR0110246A (en) 2003-03-05
AU5227201A (en) 2001-11-07
RU2353618C2 (en) 2009-04-27
KR100904101B1 (en) 2009-06-24
CA2406392C (en) 2011-08-30
EP1280776B1 (en) 2009-10-21
ES2334433T3 (en) 2010-03-10
ATE446288T1 (en) 2009-11-15
KR20020093946A (en) 2002-12-16
WO2001081311A1 (en) 2001-11-01
CA2406392A1 (en) 2001-11-01

Similar Documents

Publication Publication Date Title
CN1426396A (en) Substituted benzoic acid amides and use for inhibition of angiogenesis thereof
CN1237062C (en) Ortho-substituted anthranilic acid amides and their use as medicaments
CN1325384A (en) Anthranilic acid amides and the use thereof as medicaments
CN1429200A (en) Anthranyl amides and their use as medicaments
CN1271067C (en) Substituted 2-(2,6-dioxo-3-fluoropiperidin-3-yl)-isoindolines and their use to reduce TNF & alpha levels
CN1042331C (en) Indole derivatives
CN1066718C (en) Vasoconstrictive substituted aryloxyalkyl diamines
CN1849310A (en) Thiazole derivatives as cannabinoid receptor modulators
CN1106387C (en) PDE IV inhibiting 2-cyanoiminoimidazole derivs.
CN1145618A (en) New piperidine derivatives
CN1061035C (en) Phenylalkanolamine derivatives
CN1013864B (en) Antipsychotic gamma-carbolines
CN1080289A (en) 3- (1H-tetrazol-5-yl) -4H-pyrido [1, 2-a ] pyrimidin-4-ones, pharmaceutical compositions containing them and process for their preparation
CN87104099A (en) Anti-allergic and antiphlogistic medicament
CN1049660C (en) New benzopyran compounds, process for their preparation and the pharmaceutical compositions which contain them
CN1019010B (en) Process for preparing substituted beta-diketones
CN1044241C (en) Oxopyridinylquinoxaline derivative
CN1307567A (en) 1,5 benzodiazepine derivatives
CN1048728C (en) New 3-substituted 3H-2,3-benzodiazepine derivatives, their preparation and use as medicaments
CN1046726C (en) Imidazopyridine-pyrrolidone and imidazopyridine-oxaolidone
CN1176637A (en) Piperazine-2, 5 -dione derivatives as modulators of multidrug resistance
CN1533378A (en) Process for production of quinazolines
CN1090627C (en) New 2-amino-1,2-indene compounds, process for their preparation and pharmaceutical compositions containing them
CN1192025C (en) Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids
CN1307563A (en) N-phenyl-N'-phenylpropylpiperazine derivatives and process for the preparation thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20061122